Method for the synthesis of compounds of formula 1 and derivatives thereof

ABSTRACT

Mono-substituted and di-substituted alpha-amino acids and derivatives thereof, substituted at the alpha positon with one (mono-) or two (di-) substituents (R 2  and/or R 3 ) as shown in Formula 1: N(R 4 R 5 )C(R 2 R 3 )CO(OR 1 ).

FIELD OF THE INVENTION

[0001] The present invention relates to mono-substituted anddi-substituted alpha-amino acids and derivatives thereof, such as butnot limited to esters, amides and salts. The alpha-amino acid compoundsand their derivative compounds are substituted at the alpha positionwith one (mono-) or two (di-) substituents (R² and/or R³) as shown inFormula 1 below:

N(R⁴R⁵)C(R²R³)CO(OR¹)  Formula 1

[0002] where the moieties R¹, R², R³, R⁴, and R⁵ are as defined below.Mono-substituted and di-substituted alpha-amino acids and derivativesthereof are useful, for instance, as raw materials for pharmaceuticaland agro-chemical products. Table of Abbreviations Ac acetyl Allocallyloxycarbonyl Bn benzyl BOC tert-butyloxycarbonyl CBZbenzyloxycarbonyl Et ethyl Fmoc 9-fluorenylmethyloxycarbonyl h hour IRinfrared MS mass spectroscopy Me methyl mL milliliter NMR nuclearmagnetic resonance OTBDMS tert-butyl dimethyl silyl Ph phenyl RT roomtemperature Su succinamide t-Bu tertiary-butyl

BACKGROUND OF THE INVENTION

[0003] As reported in the literature, a number of routes are known forthe synthesis of alpha-amino acids. The best-known route is the Streckersynthesis route (see, Introduction to Organic Chemistry, Streitwieserand Heathcock, Macmillan Publishing Co., Inc. New York, 1981). In thismethod a suitable aldehyde is treated with ammonia and HCN, so that analpha-amino nitrile is formed, which is subsequently subjected to ahydrolysis reaction to provide the corresponding alpha-amino acid.

[0004] Also, it has been shown (see, Ugi, I. Angew. Chem., Intl. Ed.Engl., 1982, Vol. 21, pp. 810-819, and Ugi, I. et al., J. Prokt. Chem.,1997, Vol. 339, p. 499) that the reaction of an isocyanide (X¹NC) with acarboxylic acid (X²COOH), an aldehyde (X³CHO) and an amine (X⁴NH₂) underthe appropriate conditions provided the corresponding dipeptide(N-alkyl-N-acyl-alpha amino amide) as follows:

X¹—NC+X²—COOH+X³—CHO+X⁴NH₂→X²—CO—NX⁴—CHX³—CO—NX¹H

[0005] N-alkyl-N-acyl-alpha amino amide (i.e., a dipeptide)

[0006] In an attempt to convert the dipeptides to their correspondingalpha-amino acids, Ugi used chiral ferrocenylamine in theabove-mentioned reaction. The desired amino acids were obtained with lowto modest diastereoselectiveity. (See, Ugi I. et al., Tetrahedron Lett.,1986, Vol. 42, pp. 5931-5940).

[0007] Furthermore, the use of a convertible isocyanide in the Ugireaction, namely cyclohexene-isocyanide, followed by hydrolysis toprovide the corresponding peptide carboxylic acid, has been demonstrated(see, Armstrong, R. W. et al., J. Am. Chem. Soc., 1996, Vol. 118, p.2574) as follows:

[0008] N-alkyl-N-acyl-alpha amino acid (i.e., a peptide carboxylic acid)

[0009] In addition, the use of phenyl-isocyanide and pyridyl-isocyanidewas demonstrated in the conversion of dipeptides made by Ugi intopyrrole derivatives (see, Mjalii, et al., Tet. Lett., 1996, Vol.37,pp.2943-2946).

[0010] Moreover, the use of sugar derivatives (protectedgalactososylamine and arabinopyranosylamine) as chiral amines witht-butyl-isocyanide converted the dipeptides made by Ugi into thecorresponding sugar dipeptides, which were then converted in fourchemical steps:

[0011] (1) HCl, MeOH, 0° C. to RT, 4 h;

[0012] (2) H₂O, 12 h, RT;

[0013] (3) 6N HCl, 80° C., 24 h; and

[0014] (4) Amberlite, IR 200

[0015] using very harsh conditions to the corresponding alpha-aminoacids as shown below:

X²—CO—N(sugar)-CHX³—CO—NH—C(CH₃)₃→NH₃Cl—CHX³—COOH

[0016] where used was an aldehyde, X³CHO, where X³=Ph, t-Bu, (CH₂)₃COOH, Bn, or para-Cl-Ph (see, Kunz, H. et al., Tet. Lett., 1988, Vol.29, p. 5487, and Kunz, H. et al., Tet. Lett., 1989, Vol. 30, pp.4109-4110).

[0017] This sugar amine was also described being made by utilizingdifferent isocyanides and then being converted in three chemical steps:

[0018] (1) HCl, MeOH, 0° C. to RT, 4 h;

[0019] (2) H₂O, 12 h, RT; and

[0020] (3) 2N HCl, 60° C., 24 h

[0021] as shown below:

[0022] where used was an aldehyde, X³CHO, where X³=Ph, t-Bu, (CH₂)₄COOH,Bn, or H₂CF═CH (see, Linderman, R. J., J. Am. Chem. Soc., 1999, Vol. 64,pp. 336-337).

[0023] Also, it has been reported (see, Ugi et al., Angew. Chem. Intl.Ed. Engl., 1996, Vol. 35, p.173) that the reaction of unprotectedalpha-amino acids (namely valine, phenyl alanine and proline) with aseries of isocyanides and aldehydes in MeOH provided the correspondingthree amino peptides with excellent yield and good diastereoselectivityas shown below:

X⁴—NC+NH₂—CXH—COOH+X³—CHO→X⁴—NH—CO—CHX³—NH—CHX—COOMe

[0024] N-alkyl-N-acyl-alpha amino amide

[0025] More specifically, the synthesis of the following three compoundshas been reported by this method:

SUMMARY AND OBJECTS OF THE INVENTION

[0026] The present invention provides mono-substituted anddi-substituted alpha-amino acids and derivatives thereof, such as butnot limited to esters, amides and salts. The alpha-amino acids and theirderivatives are of Formula 1 and are substituted at the alpha positionwith one or two substituents as shown below:

N(R⁴R⁵)C(R²R³)CO(OR¹)  Formula 1

[0027] where R¹, R², and R³ are the same or different and are selectedfrom:

[0028] (a) H, with the proviso that at least one of R² and R³ is not H,

[0029] (b) mono-, di-, and tri-substituted aryl, and

[0030] (c) C₁-C₁₀ alkyl, C₁-C₁₀ substituted alkyl, C₁-C₁₀ substitutedalkyl-aryl, C₁-C₁₀ substituted alkenyl, and C₁-C₁₀ substituted alkenylaryl,

[0031] where the substituents of (b) and (c) are selected from:

[0032] H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C₁-C₁₀alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl, C₁-C₁₀ alkylamino,C₁-C₁₀ aminoalkyl aryl, C₁-C₁₀ aminocarbonyl, C₁-C₁₀aminocarbonylalkyl-aryl, C₁-C₁₀ thioalkyl, C₁-C₁₀ thioalkyl-aryl, C₁-C₁₀alkylsulfoxide, C₁-C₁₀ alkylsulfone, C₁-C₁₀ alkylsulfonamide, C₁-C₁₀alkylsulfonamide aryl, C₁-C₁₀ alkylsulfoxide aryl, C₁-C₁₀ alkylsulfonearyl, C₁-C₁₀ alkyl, aminocarbonylamino C₁-C₁₀ alkyl, C₁-C₁₀ alkylaminocarbonylamino C₁-C₁₀ alkyl aryl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀alkyl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀ alkyl aryl, C₁-C₁₀ carboxyalkyl,C₁-C₁₀ carboxyalkyl aryl, C₁-C₁₀ carbonylalkyl, C₁-C₁₀ carbonylalkylaryl, C₁-C₁₀ alkyloxycarbonylamino alkyl, C₁-C₁₀ alkyloxycarbonylaminoalkyl aryl, guanidino, C₁-C₁₀ alkylCOOH, C₁-C₁₀ alkylCONH₂, C₁-C₁₀alkenylCOOH, C₁-C₁₀ alkenyl CONH₂, and

[0033] where the aryl group of (b) and (c) is selected from:

[0034] phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl,thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl; and

[0035] where R⁴ and R⁵ are the same or different and are selected from:

[0036] (d) H, and

[0037] (e) an amine protecting group.

[0038] The present invention also provides for a method for thesynthesis of compounds of Formula 1, where R¹, R², R³, R⁴, and R⁵ are asdefined above, by reacting (1) a suitable carbonyl compound, such as analdehyde or a ketone, (2) an amino acid (employed as an aminoacid/removable chiral auxiliary), and (3) a convertible isocyanide usingappropriate reaction conditions to provide compounds Formula 2 below:

[0039] that are then subjected in situ, or after isolation andpurification, to mild amide hydrolysis or cleavage to provide compoundsof Formula 1 as racemates or in optically pure form. More particularly,the method comprises:

[0040] (i) reacting an amino acid/removable chiral auxiliary or saltthereof, a convertible isocyanide, and at least one of an aldehyde and aketone, in an alcohol or alcohol-containing solvent to obtain a compoundof Formula 2

[0041] and (ii) subjecting the compound of Formula 2 to aryl aminecleavage/hydrolysis, including catalytic hydrogenation, and to amidecleavage/hydrolysis to obtain the compound of Formula 1, and preferably,step (ii) comprises that the aryl amine cleavage/hydrolysis and theamide cleavage/hydrolysis are followed by an amine protection reactionto place at least one amine protection group on the N of Formula 1.

[0042] Hence, it is an object of the invention to provide certain novelalpha-amino acids.

[0043] Some of the objects of the invention having been stated above,other objects will become evident as the description proceeds, whentaken in connection with the Laboratory Examples as best describedbelow.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention involves the preparation ofmono-substituted and di-substituted alpha-amino acids and theirderivatives as shown in Formula 1 below:

N(R⁴R⁵)C(R²R³)CO(OR¹)  Formula 1

[0045] where the alpha-amino acids and their derivatives may beN-protected with a substituent, such as but not limited totert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc),allyloxycarbonyl (Alloc), butyloxycarbonyl (CBZ) and salts thereof, asrepresented in Formula 1 by R⁴ and R⁵. The alpha position is substitutedwith one or two substituents, as represented in Formula 1 by R² and R³.The nature of the starting carbonyl (aldehyde or ketone) compoundsselected determines the nature of the desired alpha-amino acid (mono-,di-, cyclic and acylic) substituents, R² and R³. The acid functionality,as represented by R¹ in Formula 1, may be H or may be a suitablefunctional group to provide derivatives such as but not limited toesters, amides, and salts, as represented by R¹ in Formula 1.

[0046] The process according to the invention is technically simple andeconomically attractive. With the process according to the invention,high yields are obtained with a minimal number of chemical steps. Also,the process according to the invention not only provides a wide range ofcurrently available amino acids and derivatives, but also provides newamino acids and derivatives.

[0047] An amino acid/chiral auxiliary component is used in a reactionwith a carbonyl compound (a ketone or an aldehyde) and an isocyanide toprovide compounds as shown in Formula 2 below:

N(HR⁴)C(O)C(R²R³)N(H)C(HR)C(O)(OR¹)  Formula 2

[0048] that can be converted (by cleavage/hydrolysis and amineprotection) to compounds of Formula 1. Both the isocyanide portionrepresented by R⁴—NH in Formula 2 and the amino acid/removable chiralauxiliary portion represented by NHC(HR)COOR¹ in Formula 2 are convertedstepwise in any order or concurrently under mild conditions (such as butnot limited to strong acid, catalytic hydrogenation, electron transferreactions, basic conditions, or nucleophilic additions) to provide thecorresponding alpha-amino acids and their derivatives as shown inFormula 1.

[0049] Moreover, besides racemates, synthesis of an enantiomericallypure compound can result from the amino acid/removable chiral auxiliarybeing a chiral inducer chemically to provide a majority of a singleisomer of a compound of Formula 2. The major isomer can then beseparated using standard chromatography techniques or crystallizationprior to hydrolysis of both residues (the isocyanide and the chiralauxiliary) to provide an enantiomerically pure compound of Formula 2.After cleavage of the isocyanide and amino acid/removable chiralauxiliary portions, an enantiomerically pure compound of Formula 1 isobtained. Alternatively, the amino acid/removable chiral auxiliary cancreate two diastereomers of various or similar ratios of a compound ofFormula 2. The diastereomers can then be separated using standardchromatography techniques or crystallization prior to hydrolysis of bothresidues (the isocyanide and the chiral auxiliary moieties) to providean enantiomerically pure compound of Formula 2. The enantiomericallypure compound of Formula 2 then can be converted separately to anoptically pure compound of Formula 1 upon the removal of both residues(the isocyanide and the chiral auxiliary).

[0050] More particularly, the present invention provides compounds ofFormula 1

[0051] where:

[0052] R¹, R², and R³ are the same or different and are selected from:

[0053] (a) H, with the proviso that at least one of R² and R³ is not H,

[0054] (b) mono-, di- and tri-substituted aryl, and

[0055] (c) C₁-C₁₀ alkyl, C₁-C₁₀ substituted alkyl, C₁-C₁₀ substitutedalkyl-aryl, C₁-C₁₀ substituted alkenyl, and C₁-C₁₀ substituted alkenylaryl,

[0056] where the substituents of (b) and (c) are selected from:

[0057] H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C₁-C₁₀alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl, C₁-C₁₀ alkylamino,C₁-C₁₀ aminoalkyl aryl, C₁-C₁₀ aminocarbonyl, C₁-C₁₀aminocarbonylalkyl-aryl, C₁-C₁₀ thioalkyl, C₁-C₁₀ thioalkyl-aryl, C₁-C₁₀alkylsulfoxide, C₁-C₁₀ alkylsulfone, C₁-C₁₀ alkylsulfonamide, C₁-C₁₀alkylsulfonamide aryl, C₁-C₁₀ alkylsulfoxide aryl, C₁-C₁₀ alkylsulfonearyl, C₁-C₁₀ alkyl, aminocarbonylamino C₁-C₁₀ alkyl, C₁-C₁₀ alkylaminocarbonylamino C₁-C₁₀ alkyl aryl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀alkyl, C1-C₁₀ alkyloxygarbonyl C₁-C₁₀ alkyl aryl, C₁-C₁₀ carboxyalkyl,C₁-C₁₀ carboxyalkyl aryl, C₁-C₁₀ carbonylalkyl, C₁-C₁₀ carbonylalkylaryl, C₁-C₁₀ alkyloxycarbonylamino alkyl, C₁-C₁₀ alkyloxycarbonylaminoalkyl aryl, guanidino, C₁-C₁₀ alkylCOOH, C₁-C₁₀ alkylCONH₂, C₁-C₁₀alkenylCOOH, C₁-C₁₀ alkenyl CONH₂, and the like,

[0058] and where the aryl group of (b) and (c) is selected from:

[0059] phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl,thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and thelike, and

[0060] where:

[0061] R⁴ and R⁵ are the same of different and are selected from:

[0062] H and an amine protecting group such as but not limited tophenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ and thelike.

[0063] Optionally, R² and R³ in Formula 1 are joined together to formcyclic compounds of Formula 1a with a ring size of 3-8 as follows:

[0064] For instance, the ring system may be selected fromsubstituted-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl as shown in compounds of Formulae 1b and 1cas follows:

[0065] selected from substituted-cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl as incompounds of Formula 1d as follows:

[0066] where R⁶ and R⁷, R⁶ and R¹⁰, or R⁹ and R¹⁰ may be joined togetheras a ring to form a fused system with the cyclopentene ring, where thearyl and its substituents are as defined below vis-à-vis (e) and (f),

[0067] or selected from substituted heterocyclic compounds, where A isO, S, SO, SO₂, NH, SO₂NHR⁸, NCONHR⁸, NCOOR⁸, or NR⁸ inserted in the ringsystems as in compounds of Formulae 1e and 1f as follows:

[0068] where the substituents R⁴ and R⁵ in Formulae 1a-1f are as definedabove and where the substituents (R⁶, R⁷, R⁸, R⁹, and R¹⁰) in Formulae1a-1f are the same or different and are selected from:

[0069] (d) H,

[0070] (e) mono-, di-, and tri-substituted aryl, and

[0071] (f) C₁-C₁₀ substituted alkyl, C₁-C₁₀ substituted alkyl-aryl,C₁-C₁₀ substituted alkenyl, and C₁-C₁₀ substituted alkenyl aryl, wherethe substituents of (e) and (f) are selected from:

[0072] H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C₁-C₁₀alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl, C₁-C₁₀ alkylamino,C₁-C₁₀ aminoalkyl aryl, C₁-C₁₀ aminocarbonyl, C₁-C₁₀aminocarbonylalkyl-aryl, C₁-C₁₀ thioalkyl, C₁-C₁₀ thioalkyl-aryl, C₁-C₁₀alkylsulfoxide, C₁-C₁₀ alkylsulfone, C₁-C₁₀ alkylsulfonamide, C₁-C₁₀alkylsulfonamide aryl, C₁-C₁₀ alkylsulfoxide aryl, C₁-C₁₀ alkylsulfonearyl, C₁-C₁₀ alkyl, aminocarbonylamino C₁-C₁₀ alkyl, C₁-C₁₀ alkylaminocarbonylamino C₁-C₁₀ alkyl aryl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀alkyl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀ alkyl aryl, C₁-C₁₀ carboxyalkyl,C₁-C₁₀ carboxyalkyl aryl, C₁-C₁₀ carbonylalkyl, C₁-C₁₀ carbonylalkylaryl, C₁-C₁₀ alkyloxycarbonylamino alkyl, C₁-C₁₀ alkyloxycarbonylaminoalkyl aryl, guanidino, C₁-C₁₀ alkylCOOH, C₁-C₁₀ alkylCONH₂, C₁-C₁₀alkenylCOOH, C₁-C₁₀ alkenyl CONH₂, and the like,

[0073] and where the aryl group of (e) and (f is selected from:

[0074] phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl,thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and thelike.

[0075] The invention relates to a synthesis where a convertibleisocyanide, such as but not limited to cyclohexenyl, t-butyl,cyclohexyl, or phenyl, is used in conjunction with an appropriate“chiral auxiliary” as an amino acid input (amino acid/removable chiralauxiliary) in the three component condensation reaction to provide(after hydrolysis of both the amine and isocyanide moieties) thecorresponding alpha-amino acids and their derivatives as represented byFormula 1.

[0076] Compounds of Formula 1 are synthesized according to the followingreaction mechanism:

[0077] It is noted that when proceeding from Formula 2 to Formula 1, 1)may be performed prior to 2), 2) may be performed prior to 1), or 1) and2) may be performed concurrently.

[0078] Reaction of an appropriate aldehyde or ketone (such as but notlimited to phenyl-acetaldehyde or cyclohexanone) with an aminoacid/removable chiral auxiliary or salt thereof (such as but not limitedto phenyl glycine, i.e., R is phenyl) and an appropriate convertibleisocyanide (such as but not limited to R⁴ is phenyl-, cyclohexenyl-,cyclohexyl-, or t-butyl-) utilizing an appropriate solvent and reactionconditions (such as but not limited to R¹OH is methanol, ethanol, orisopropanol, at about 80° C. to 220° C.) provided compounds of Formula2. Then, after cleavage of both the chiral auxiliary amine and the amideportions, compounds of Formula 2 provided the corresponding alpha-aminoacids and their derivatives of Formula 1.

[0079] The desired alpha-amino acid of Formula 2 has a removable aminoacid/chiral auxiliary and preferably is selected from compounds where Ris mono, di-, tri-, tetra- or penta-substituted aryl, where the aryl isselected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, and the like, andthe subsbtuents are selected from: H, cyano, amino, C₁-C₁₀ alkyl, C₁-C₁₀alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl, C₁-C₁₀ alkylamino,C₁-C₁₀ aminoalkyl aryl, and the like.

[0080] As shown in the Laboratory Examples below, compounds of Formula 2were separated using standard separation techniques, such as but notlimited to chromatography separation and crystallization, to provideenantiomerically pure compounds of Formula 2. Then, the enantiomericallypure compounds of Formula 2 were subjected to amide cleavage conditions,such as but not limited to acidic reaction conditions, such as HCl/MeOHor aqueous HCl, to provide the corresponding acid, followed by benzylamine or derivative cleavage conditions, such as but not limited to acatalytic hydrogenation reaction, such as but not limited to H₂ withPd(OH)₂ on carbon, to provide the corresponding amine, followed byacidic hydrolysis such as HCl/methanol or aqueous HCl to provide thecorresponding enantiomerically pure amino acids of Formula 1.

[0081] Compounds were synthesized in accordance with the followingLaboratory Examples.

LABORATORY EXAMPLES Example I Preparation of Intermediary Compound ofFormula 2

[0082] Several compounds of Formula 2, where R¹ was Me, were synthesizedaccording to Scheme 1 as follows:

[0083] General Procedure

[0084] To a cooled mixture of an amino acid (1 mmol) in methanol (8 mL),at −78° C., was added an aldehyde or a ketone (1 mmol in 1 mL of MeOH)and an isocyanide (1 mmol in 1 mL MeOH). Each respective resultingmixture was allowed to warm to room temperature or reflux and stirbetween 3 h to 48 h. The crude reaction for each was concentrated anddissolved in 10 ml of Et₂O. After filtration (to remove the remainingamino acid), each respective filtrate was concentrated and purified bycolumn chromatography on silica gel, resulting in the followingcompounds of Formula 2:

[0085] 84% yield (at 92% conversion), ratio 3:2. MS (ESP+) m/z 471.20,(MH⁺) 493.16 (M+Na).

[0086] H1 NMR (CD₃OD, 300 MHz, major diastereoisomer): δ 7.77 (dd, 1H),7.45-7.10 (m, 8H), 4.84 (d, 1H, 13.3 Hz), 4.72 (d, 1H, 13.3 Hz), 4.47(s, 1H), 3.64 (s, 3H), 2.95 (t, 1H, 6.4 Hz), 1.73 (dq, 2H), 0.95 (t, 3H,7.4 Hz), 0.88 (s, 9H), 0.08 (s, 3H), 0.03 (s, 3H).

[0087] H1 NMR (CD₃OD, 300 MHz, minor diastereoisomer): δ 7.77 (dd, 1H),7.45-7.10 (m, 8H), 4.60 (d, 1H, 13.3 Hz), 4.52 (d, 1H, 13.3 Hz), 4.41(s, 1H), 3.69 (s, 3H), 3.16 (t, 1H, 6.4 Hz), 1.83 (dq, 2H), 1.05 (t, 3H,7.4 Hz), 0.81 (s, 9H), −0.02 (s, 3H), −0.07 (s, 3H).

[0088] 70% yield, ratio 2:1. MS (ESP+) m/z 525.37 (MH⁺).

[0089] H1 NMR (CD₃OD, 300 MHz, major diastereoisomer): δ 7.75 (dd, 1H),7.42-7.10 (m, 8H), 4.85 (d, 1H, 13 Hz), 4.72 (d, 1H, 13 Hz), 4.40 (s,1H), 3.64 (s, 3H), 2.79 (d, 1H, 5.9 Hz), 1.9-1.5 (m, 1H), 0.88 (s, 9H),0.09 (s, 3H), 0.03 (s, 3H).

[0090] H1 NMR (CD₃OD, 300 MHz, minor diastereoisomer): δ 7.77 (dd, 1H),7.45-7.10 (m, 8H), 4.56 (d, 1H, 13 Hz), 4.50 (d, 1H, 13 Hz), 4.36 (s,1H), 3.68 (s, 3H), 3.03 (d, 1H, 5.9 Hz), 1.9-1.5 (m, 1H), 1.05 (t, 3H),0.82 (s, 9H), −0.02 (s, 3H), −0.06 (s, 3H).

[0091] 75% yield (at 93% conversion). MS (ESP+) m/z 511.71 (MH⁺).

[0092] H1 NMR (CD₃OD, 300 MHz): δ 7.66 (dd, 1H, 8.6-1.3 Hz), 7.39 (dd,2H, 7.7-2 Hz), 7.31-7.17 (m, 5H), 7.06 (dt, 1H, 7.7-1.3 Hz), 4.49 (d,1H, 13 Hz), 4.40 (s, 1H), 4.28 (d, 1H, 13 Hz), 3.58 (s, 3H), 2.1-1.3 (m,10H), 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H).

[0093] 88% yield. MS (ESP+) m/z 569.71. (MH⁺) 591.21 (M+Na).

[0094] H1 NMR (CD₃OD, 300 MHz): δ 7.67 (dd, 1H, 8.8-1.5 Hz), 7.40 (dd,2H, 7.8-1.8 Hz), 7.32-7.20 (m, 5H), 7.08 (dt, 1H, 7.6-1.3 Hz), 4.53 (d,1H, 13.5 Hz), 4.38 (s, 1H), 4.36 (d, 1H, 13.5 Hz), 3.90 (s, 2H), 3.59(s, 3H), 2.19 (m, 1H), 2.04 (m, 1H), 1.90-1.48 (m, 6H), 0.89 (s, 9H),0.06 (s, 3H), 0.03 (s, 3H).

[0095] 71% yield (at 69% conversion). MS (ESP+) m/z 513.68 (MH⁺). H1 NMR(CD₃OD, 300 MHz): δ 7.67 (dd, 1H, 8.5-1.5 Hz), 7.41 (dd, 2H, 7.9-1.9Hz), 7.33-7.21 (m, 5H), 7.10 (dt, 1H, 7.6-1.4 Hz), 4.54 (d, 1H, 13.2Hz), 4.43 (s, 1H), 4.37 (d, 1H, 13.2 Hz), 3.9-3.55 (m, 4H), 3.60 (s,3H), 2.25-1.65 (m, 4H), 0.88 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H).

[0096] 99% yield (at 53% conversion). MS (ESP+) m/z 529.43 (MH⁺), 551.17(M+Na). H1 NMR (CD₃OD, 300 MHz): δ 7.67 (dd, 1H, 8.8-1.6 Hz), 7.41 (dd,2H, 7.7-1.9 Hz), 7.33-7.20 (m, 5H), 7.09 (dt, 1H, 7.6-1.4 Hz), 4.53 (d,1H, 13.4 Hz), 4.41 (s, 1H), 4.36 (d, 1H, 13.4 Hz), 3.60 (s, 3H), 3-2.8(m, 2H), 2.78-2.55 (m, 2H), 2.5-2.15 (m, 2H), 2.05-1.8 (m, 2H), 0.89 (s,9H), 0.06 (s, 3H), 0.04 (s, 3H).

[0097] 75% yield, ratio 2:1. H1 NMR (CDCl₃, 300 MHz, majordiastereoisomer): δ 8.21 (d, 1H), 7.36-7.03 (m, 13H), 6.88 (dd, 1H),4.77 (d, 1H, 12.9 Hz), 4.60 (d, 1H, 12.9 Hz), 4.35 (br d, 1H, 9 Hz),3.61 (s, 3H), 3.24 (dd, 1H), 3.17 (dd, 1H), 2.74 (dd, 1H), 2.64 (br d,1H), 0.89 (s, 9H), 0.07 (s, 3H), −0.02 (s, 3H). MS (ESP+) m/z 533.69(MH⁺), 555.21 (M+Na).

[0098] H1 NMR (CD₃OD, 300 MHz, minor diastereoisomer): δ 8.15 (d, 1H),7.37-7.11 (m, 12H), 7.11 (dd, 1H), 7.03 (td, 1H), 4.42 (d, 1H, 13.7 Hz),4.33 (d, 1H, 13.7 Hz), 4.30 (br, 1H), 3.56 (s, 3H), 3.50 (dd, 1H), 3.28(dd, 1H), 2.95 (dd, 1H), 2.66 (br, 1H), 0.80 (s, 9H), −0.06 (s, 3H),−0.12 (s, 3H). MS (ESP+) m/z 533.70 (MH⁺), 555.18 (M+Na).

[0099] 88% yield (at 85% conversion). MS (ESP+) m/z 547.70 (MH⁺), 569.22(M+Na). H1 NMR (CDCl3, 300 MHz, mixture of diastereoisomers 2:2:1): δ7.98, 7.83 and 7.76 (d, 1H), 7.61, 7.50 and 7.42 (d, 1H), 7.35-6.88 (m,12H), 4.76 and 4.64 (d, 2H), 4.44 (d, 1H), 4.31, 4.26, and 4.14 (s, 1H),3.59 and 3.56 (s, 3H), 3.34 (m, 1H), 1.45 and 1.38 (d, 3H), 0.92, 0.89and 0.85 (s, 9H), 0.11, 0.10 and 0.01 (s, 3H), 0.05, 0.03 and −0.02 (s,3H).

[0100] quantitative yield, ratio 7:3. MS (ESP+) m/z 369.24 (MH⁺), 391.21(M+Na).

[0101] H1 NMR (CDCl3, 300 MHz, major diastereoisomer): δ 7.36-7.13 (m,8H), 6.87 (d, 2H), 4.11 (s, 1H), 3.55 (s, 3H), 3.24 (dd, 1H, 9.9-4.2Hz), 3.18 (dd, 1H, 13.6-4.2 Hz), 2.80 (dd, 1H, 13.6-9.9 Hz), 1.19 (s,9H).

[0102] H1 NMR (CD₃OD, 300 MHz, minor diastereoisomer): δ 7.36-7.13 (m,8H), 7.08 (d, 2H), 4.14 (s, 1H), 3.62 (s, 3H), 3.12 (dd, 1H, 13.6-4.2Hz), 2.97 (dd, 1H, 9.9-4.2 Hz), 2.63 (dd, 1H, 13.6-9.9 Hz), 1.36 (s,9H).

[0103] 79% yield, ratio 2:1. MS (ESP+) m/z 361.65 (MH⁺), 383.14 (M+Na).

[0104] H1 NMR (CD₃OD, 300 MHz, major diastereoisomer): δ 7.74 (d, 2H),7.42-7.10 (m, 7H), 4.85 (d, 1H, 13 Hz), 4.72 (d, 1H, 13 Hz), 4,40 (s,1H), 3,64 (s, 3H), 2.79 (d, 1H, 5.9 Hz), 1.72 (m, 11H), 0.88 (s, 9H),0.09 (s, 3H), 0.03 (s, 3H).

[0105] H1 NMR (CD₃OD, 300 MHz, minor diastereoisomer): δ 7.76 (d, 2H),7.42-7.10 (m, 7H), 4.56 (d, 1H, 13 Hz), 4.50 (d, 1H, 13 Hz), 4.36 (s,1H), 3.68 (s, 3H), 3.03 (d, 1H, 5.9 Hz), 1.72 (m, 11H), 0.82 (s, 9H),−0.02 (s, 3H), −0.06 (s, 3H).

[0106] 77% yield (at 40% conversion).

[0107] H1 NMR (CDCl3, 300 MHz): δ 7.42-7.27 (m, 5H), 4.22 (s, 1H), 3.66(s, 3H), 2.94 (br s, 1H), 2.33 (m, 1H), 2.07 (m, 1H), 1.90-1.20 (m, 8H),1.02 (s, 9H). MS (ESP+) m/z 347.64 (MH⁺), 369.17 (M+Na).

[0108] 81% yield (at 64% conversion).

[0109] H1 NMR (CDCl3, 300 MHz): δ 7.40-7.26 (m, 5H), 6.60(br s, 1H),3.90 (m, 4H), 3.64 (s, 3H), 2.50 (t, 2H, 6.9 Hz), 2.00 (t, 2H, 6.9 Hz),1.62 (m, 4H), 1.06 (s, 9H). MS (ESP+) m/z 405.68.

[0110] 77% yield (at 50% conversion).

[0111] H1 NMR (CDCl3, 300 MHz): δ 7.42-7.35 (m, 5H), 6.61 (s, 1H), 4.25(s, 1H), 3.93 (m, 2H), 3.68 (m, 2H), 3.67 (s, 3H), 2.30 (ddd, 1H), 1.98(ddd, 1H), 1.57-1.42 (2H), 1.07 (s, 9H). MS (ESP+) m/z 349.19 (MH⁺),371.17 (M+Na).

[0112] quantitative yield (at 40% conversion).

[0113] H1 NMR (CDCl₃, 300 MHz) δ 7.4-7.27 (m, 5H), 6.54 (br s, 1H), 4.23(s, 1H), 3.67 (s, 3H), 2.85 (m, 2H), 2.58 (m, 2H), 2.40 (m, 1H), 2.15(m, 1H), 1.80 (m, 2H). MS (ESP+) m/z 365.17 (MH⁺), 387.17 (M+Na).

[0114] 58% yield. MS (ESP+) m/z 368.24 (MH⁺).

[0115] H1 NMR (CDCl3, 300 MHz) δ 7.42-7.25 (m, 5H), 6.62 (s, 1H), 4.24(d, 1H), 3.04 (dt, 1H), 2.93-2.70 (m, 5H), 2.20 (ddd, 1H), 1.90 (ddd,1H), 1.10 (s, 9H).

[0116] 88% yield, ratio 2:1. MS (ESP+) m/z 321.26 (MH⁺), 343.22 (M+Na).

[0117] H1 NMR (CDCl3, 300 MHz, major diastereoisomer): δ 7.40-7.27 (m,5H), 6.90 (s, 1H), 4.18 (s, 1H), 3.68 (s, 3H), 2.85 (d, 1H, 4.5 Hz),2.12 (m, 1H), 1.21 (s, 9H), 1.04 (d, 3H, 6.9 Hz), 0.93 (d, 3H, 6.9 Hz).

[0118] H1 NMR (CDCl₃, 300 MHz, minor diastereoisomer): δ 7.40-7.27 (m,5H), 6.86 (s, 1H), 4.22 (s, 1H), 3.64 (s, 3H), 2.57 (d, 1H, 4.5 Hz),2.02 (m, 1H), 1.37 (s, 9H), 0.85 (d, 3H, 6.9 Hz), 0.83 (d, 3H, 6.9 Hz).

[0119] 61% yield, ratio 4:3. MS (ESP+) m/z 356.21 (MH⁺), 378.17 (M+Na).

[0120] H1 NMR (CDCl3, 300 MHz, major diastereoisomer): δ 8.55 (m, 1H),7.66 (m, 1H), 7.54 (m, 1H), 7.38-7.25 (m, 5H), 7.20 (m, 1H), 4.36 (s,1H), 4.17 (s, 1H), 3.65 (s, 3H), 1.21 (s, 9H).

[0121] H1 NMR (CDCl3, 300 MHz, minor diastereoisomer): δ 8.50 (m, 1H),7.59 (m, 1H), 7.47 (m, 1H), 7.38-7.25 (m, 5H), 7.16 (m, 1H), 4.44 (s,1H), 4.06 (s, 1H), 3.69 (s, 3H), 1.32 (s, 9H).

[0122] 48% yield, ratio 3:2. MS (ESP+) m/z 356.67 (MH⁺), 378.19 (M+Na).

[0123] H1 NMR (CDCl3, 300 MHz, major diastereoisomer): δ 8.47 (d, 1H),8.52 (dd, 1H), 7.68 (dt, 1H), 7.58 (dt, 1H), 7.39-7.21 (m, 5H), 6.99 (brs, 1H), 4.33 (s, 1H), 4.00 (s, 1H), 3.70 (s, 3H), 1.36 (s, 9H).

[0124] H1 NMR (CDCl₃, 300 MHz, minor diastereoisomer): δ 8.60 (d, 1H),8.56 (dd, 1H), 7.49 (dt, 1H), 7.47 (dt, 1H), 7.39-7.21 (m, 5H), 7.01 (brs, 1H), 4.28 (s, 1H), 4.08 (s, 1H), 3.70 (s, 3H), 1.27 (s, 9H).

[0125] 50% yield, ratio 1:1 MS (ESP+) rm/z 356.24 (MH⁺), 378 (M+Na).

[0126] H1 NMR (CDCl3, 300 MHz, mixture of diastereoisomers): δ 8.59 and8.53 (d, 1H, 6.1 Hz), 7.39-7.25 (m, 5H), 7.18 and 7.14 (d, 2H), 6.94 and6.84 (br s, 1H), 4.31 and 4.27 (s, 1H), 4.04 and 3.97 (s, 1H), 3.71 (s,3H), 1.34 and 1.25 (s, 9H).

[0127] 40% yield, ratio 1:1. MS (ESP+) m/z 351.13 (MH⁺), 373.12 (M+Na).

[0128] H1 NMR (CDCl3, 300 MHz): δ 7.43-7.23 (m, 5H), 4.23 and 4.20 (s,1H), 3.67 and 3.66 (s, 3H), 3.21 (s, 2H), 3.03 (t, 2H, 7.2 Hz), 2.59 (t,2H, 7.2 Hz), 1.13 and 1.02 (s, 9H).

[0129] quantitative yield, ratio 1:1.

[0130] H1 NMR (CDCl3, 300 MHz): δ 7.42-7.08 (m, 8H), 6.89 (d, 2H), 4.20(s, 1H), 3.67 and 3.60 (s, 3H), 3.40 and 3.12 (dd, 1H, 8.2-4.5 Hz), 3.26and 3.20 (dd, 1H, 13.8-4.5), 2.89 and 2.68 (dd, 1H, 13.8-8.2 Hz),1.99-0.85 (m, 10H).

[0131] quantitative yield, ratio 2:1. MS (ESP+) m/z 393.19 (MH⁺), 415.17(M+Na).

[0132] H1 NMR (CDCl3, 300 MHz, major diastereosiomer): δ 8.00 (s, 1H),7.39-7.36 (m, 10H), 6.07 (m, 1H), 4.15 (s, 1H), 3.54 (s, 3H), 3.35 (dd,1H, 8.6-4.0 Hz), 3.25 (dd, 1H, 13.7-4.0 Hz), 2.82 (dd, 1H, 13.7-8.6 Hz),2.08 (m, 2H), 1.90 (m, 2H), 1.57 (m, 4H).

[0133] H1 NMR (CDCl3, 300 MHz, minor diastereosiomer): δ 8.35 (s, 1H),7.27-7.03 (m, 8H), 6.78 (d, 2H0, 6.22 (m, 1H), 4.15 (s, 1H), 3.61 (s,3H0, 3.20 (dd, 1H, 13.8-4.0 Hz), 3.08 (dd, 1H, 9.9-4.0 Hz), 2.61 (dd,1H, 13.8-9.9 Hz), 2.15 (m, 3H), 1.78-1.56 (m, 5H).

[0134] 86% yield. MS (ESP+) m/z 438.65 (MH⁺).

[0135] MS (ESP+) m/z 438.33.

[0136] NMR, MS, IR and yield not determined.

[0137] MS (ESP+) m/z 424.25 (MH⁺).

Example II Preparation of Intermediary Compound of Formula 3 andConversion Thereof Into Desired Compound of Formula 1

[0138] The respective compounds of Formula 3 were obtained according toScheme 2 as follows:

[0139] General Procedure

[0140] Several of the compounds of Formula 2 (made as shown above inExample I) were each respectively dissolved in MeOH (10 mL/mmol) andPd(OH)₂ (0.2 to 0.8 eq) was added. Each respective mixture was degassedand H₂ gas was added. This procedure was repeated three times. Then,each respective mixture was allowed to stir under a H₂ atmosphere untilthe reaction was complete.

[0141] Each respective crude concentrate mixture was filtered throughCelite™ and washed with MeOH (10 ml/mmol). Each respective filtrate wasconcentrated to lead to a crude.

[0142] Each respective crude concentrate was dissolved in Et₂O andwashed with 2N HCl (10 mL/mmol) twice. The combined aqueous layers werebasified to pH˜8 by addition of K₂CO₃ solid, and then extracted withEt₂O (10 mL/mmol) twice. The combined organic layers were dried overNa₂SO₄ and concentrated to lead to the desired products of Formula 3 asfollows:

[0143] 73% yield. MS (ESP+) m/z 231.17 (M+Na).

[0144] H1 NMR (CD₃OD, 300 MHz): δ 7.74 (d, 1H, 8.4 Hz), 7.38 (d, 1H, 8.4Hz), 7.30 (td, 1H, 7.6-1.7 Hz), 7.17 (td, 1H, 7.6-1.7 Hz), 4.64 (s, 2H),3.44 (dd, 1H, 6-6.6 Hz), 1.86 (m, 1H), 1.70 (m, 1H), 1.05 (t, 3H).

[0145] 57% yield.

[0146] H1 NMR (CD₃OD, 300 MHz): δ 7.67 (dd, 1H), 7.34-7.22 (m, 7H), 7.13(td, 1H), 4.40 (s, 2H), 3.72 (dd, 1H, 7.6-6.1 Hz), 3.11 (dd, 1H,13.4-6.1 Hz), 2.94 (dd, 1H, 13.4-7.6 Hz). MS (ESP+): m/z 271.04 (MH⁺),293.04 (M+Na).

[0147] 72% yield.

[0148] H1 NMR (CD₃OD, 300 MHz): δ 7.73 (d, 1H), 7.35-7.23 (m, 7H), 7.13(td, 1H), 4.52 (s, 2H), 3.81 (dd, 1H, 7.2-6.4 Hz), 3.14 (dd, 1H,13.3-6.4 Hz), 3.00 (dd, 1H, 13.3-7.2 Hz), 0.89 (s, 9H), 0.06(s, 3H),0.03 (s, 3H). MS (ESP+): m/z 385.29 (MH⁺), 407.30 (M+Na).

[0149] NMR, MS, IR and yield not determined.

[0150] NMR, MS, IR and yield not determined.

[0151] 95% yield.

[0152] H1 NMR (CD₃OD, 300 MHz): δ 7.68 (dd, 1H, 8.1-0.9 Hz), 7.20 (d,1H, 8.1), 7.16 (t, 1H, 8.1), 7.05 (dt, 1H, 8.1-0.9 Hz), 2.26 (s, 3H),1.99 (m, 2H), 1.75-1.50 (m, 8H). MS (ESP+): m/z 233.10 (MH⁺).

[0153] 58% yield.

[0154] H1 NMR (CD₃OD, 300 MHz): δ 7.57 (d, 1H), 7.35-7.25 (m, 2H), 7.06(td, 1H), 4.61 (m, 4H), 2.27 (m, 2H), 2.25 (s, 3H), 1.85 (m, 2H), 1.72(m, 2H), 1.62 (m, 2H). MS (ESP+): m/z 291.07 (MH⁺).

[0155] 35% yield.

[0156] H1 NMR (CDCl3, 300 MHz, racemic): δ 7.34-7.19 (m, 5H), 3.74 (m,1H), 3.56 (dd, 1H, 9.2-4.1 Hz), 3.23 (dd, 1H, 13.9-4.1 Hz), 2.90 (dd,1H, 13.9-9.2 Hz), 1.85 (m, 2H), 1.68 (m, 2H), 1.6-1.07 (m, 6H).

[0157] 77% yield.

[0158] H1 NMR (CD₃OD, 300 MHz, racemic): δ 7.30-7.13 (m, 5H), 3.43 (m,1H), 2.90 (dd, 1H), 2.77 (dd, 1H), 1.21 (s, 9H).

[0159] 71% yield.

[0160] H1 NMR (CD₃OD, 300 MHz): δ 1.85 (m, 2H), 1.68-1.44 (m, 8H), 1.30(s, 9H). MS (ESP+): m/z 199.22 (MH⁺), 221.21 (M+Na).

[0161] 88% yield.

[0162] H1 NMR (CD₃OD, 300 MHz): δ 3.81-3.65 (m, 4H), 2.11 (m, 2H), 1.33(s, 9H), 1.32 (m, 2H). MS (ESP+): m/z 201.22 (MH⁺), 233.19 (M+Na).

[0163] 39% yield.

[0164] H1 NMR (CD₃OD, 300 MHz): δ 3.91 (m, 4H), 2.62 (m, 4H), 2.28 (m,4H), 1.35 (s, 9H). MS (ESP+): m/z 257.15 (MH⁺).

[0165] NMR, MS, IR and yield not determined.

[0166] quantitative yield.

[0167] H1 NMR (CD₃OD, 300 MHz): δ 2.90-2.70 (m, 4H), 2.06 (ddd, 1H),1.86 (ddd, 1H), 1.58 (m, 2H), 1.14 (s, 9H). MS (ESP+) m/z 200.06 (MH⁺).

[0168] NMR, MS, IR and yield not determined.

[0169] NMR, MS, IR and yield not determined.

[0170] NMR, MS, IR and yield not determined.

[0171] Then the respective compounds of Formula 1 were obtainedaccording to Scheme 3 as follows:

[0172] General Procedure

[0173] To each respective compound of Formula 3 was added HCl 6N (10mL/mmol) and the reaction mixture was stirred at reflux for 24 h. Next,each respective mixture was cooled to room temperature and extractedwith ether (10 mL/mmol) twice. For each, the aqueous layer was thenconcentrated to afford the following desired alpha-amino acid compoundsof Formula 1 in the form of the hydrochloride salt:

[0174] quantitative yield.

[0175] H1 NMR (CD₃OD, 300 MHz, HCl salt): δ 2.11 (m, 2H), 1.84-1.46 (m,8H). MS (ESP+): m/z 144.19 (MH+).

[0176] quantitative yield.

[0177] H1 NMR (CD₃OD, 300 MHz, HCl salt): δ 3.85 (m, 4H), 2.21 (m, 4H),1.85 (m, 4H). MS (ESP+) m/z 146.02 (MH⁺).

[0178] NMR, MS, IR and yield not determined.

[0179] quantitative yield.

[0180] H1 NMR (CD₃OD, 300 MHz, HCl salt): δ 3.93 (t, 1H, 6 Hz), 1.96 (m,2H), 1.06 (t, 3H, 7.7 Hz). MS (ESP+) m/z 104.22 (MH⁺).

[0181] quantitative yield.

[0182] H1 NMR (CD₃OD, 300 MHz, racemic HCl salt): δ 7.41-7.25 (m, 5H),4.25 (dd, 1H, 7.6-5 Hz), 3.31 (dd, 1H, 14.6-5 Hz), 3.14 (dd, 1H,14.6-7.6 Hz).

[0183] H1 NMR (CD₃OD, 300 MHz, HCl salt): δ 7.45-7.29 (m, 5H), 4.24 (dd,1H, 7.5-5.4 Hz), 3.31 (dd, 1H, 14.2-5.4 Hz), 3.16 (dd, 1H, 14.2-7.5 Hz).MS (ESP+): m/z 165.97 (MH+). α_(D)=+12 (c=0.2, H₂O).

[0184] 87% yield.

[0185] H1 NMR (CD₃OD, 300 MHz, HCl salt): δ 7.40-7.26 (m, 5H), 4.26 (dd,1H, 7.8-5.3 Hz), 3.31 (dd, 1H, 14.6-5.3), 3.14 (dd, 1H, 14.6-7.8 Hz). MS(ESP+) 166.00 (MH⁺).

[0186] 60% yield.

[0187] H1 NMR (CD₃OD, 300 MHz, HCl salt): δ 2.36-2.12 (m, 3H), 2.02-1.69(m, 5H). MS (ESP+) m/z 155.05 (M−2).

[0188] quantitative yield.

[0189] H1 NMR (CD₃OD, 300 MHz, HCl salt): δ 3.6-2.96 (m, 4H), 2.67-1.88(m, 4H).

[0190] NMR, MS, IR and yield not determined.

[0191] NMR, MS, IR and yield not determined.

[0192] NMR, MS, IR and yield not determined.

Example III Preparation of N-Protected Compound of Formula 1

[0193] N-Protection With Fmoc.

[0194] The respective N-protected compounds of Formula 1 were obtainedaccording to Scheme 4 as follows:

[0195] General Procedure

[0196] Several of the amino-acid compounds (HCl salt) of Formula 1 (madeas shown above in Example II) were respectively dissolved in a solutionof NaHCO₃ (10 mL/mmol) and a solution of FmocOSu in dioxan (10 mL/mmol)was added to each. Each mixture was stirred for 0.5 h and then dilutedwith H₂O and AcOEt (10 mL/mmol).

[0197] After extraction the aqueous layer for each was extracted withAcOEt (10 mL/mmol, twice). The combined organic layers were washed byH₂O (10 mL/mmol). The aqueous phase was acidified with a 2N HCl solutionto pH-2 and extracted with AcOEt (10 mL/mmol, twice). The combinedorganic layers were dried over Na₂SO₄ and concentrated to lead to thedesired products of N-protected Formula 1 as follows:

[0198] 61% yield.

[0199] H1 NMR (CDCl3, 300 MHz, racemic): δ 7.76 (d, 2H, 7.8 Hz), 7.55(d, 2H, 7.8 Hz), 7.40 (t, 2H, 7.8 Hz), 7.30 (dt, 2H, 7.8-1.4 Hz),7.27-7.15 (m, 5H), 5.40 (br d, 1H), 4.42 (m, 2H), 4.29 (m, 1H), 4.19 (t,1H), 1.87 (m, 1H),

[0200] 25% yield.

[0201] H1 NMR (CD₃OD, 300 MHz): δ 7.78 (d, 2H, 7.4 Hz), 7.68 (d, 2H, 7.4Hz), 7.38 (dt, 2H, 7.4-1.4 Hz), 7.30 (dt, 2H, 7.4-1.4 Hz), 4.31 (d, 2H,6.8 Hz), 4.21 (t, 1H, 6.8 Hz), 2.06 (m, 2H), 1.81 (m, 2H), 1.58 (m, 4H).MS (ESP+) m/z 366.14 (MH⁺).

[0202] 97% yield.

[0203] H1 NMR (CD₃OD, 300 MHz): δ 7.78 (d, 2H, 7.4 Hz), 7.67 (d, 2H, 7.4Hz), 7.37 (dt, 2H, 7.4-1.3 Hz), 7.29 (dt, 2H, 7.4-1.3 Hz), 4.36 (br d,2H, 6.2 Hz), 4.20 (t, 1H, 6.2 Hz), 3.74 (m, 2H), 3.60 (m, 2H), 2.08 (m,2H), 1.95 (m, 2H). MS (ESP+) m/z 368.10 (MH⁺).

[0204] 65% yield.

[0205] H1 NMR {CD₃OD, 300 MHz): δ 7.78 (d, 2H, 7.2 Hz), 7.66 (d, 2H),7.37 (t, 2H), 7.29 (dt, 2H, 7.2-1.3 Hz), 4.34 (m, 2H), 4.22 (t, 1H, 7Hz), 4.06 (dd, 1H, 5.6-9.6 Hz), 1.87 (m, 1H), 1.70 (m, 1H), 0.97 (t, 3H,7.1 Hz). α_(D)=+18 (c=0.16, DMF). MS (ESP+) m/z 326.14 (MH⁺), 348.08(M+Na).

[0206] 44% yield.

[0207] H1 NMR (CD₃OD, 300 MHz): δ 7.77 (d, 2H, 7.8 Hz), 7.58 (d, 2H, 7.8Hz), 7.38 (t, 2H, 7.8 Hz), 7.31-7.14 (m, 6H), 4.41 (dd, 1H, 9.24.8 Hz),4.34-4.10 (m, 3H), 3.20 (dd, 1H, 144.8 Hz), 2.93 (dd, 1H, 14-9.2 Hz). MS(ESP+) m/z 388.12 (MH⁺), 410.15 (M+Na).

[0208] MS (ESP+) m/z 379.21.

[0209] N-Protection With BOC.

[0210] The respective N-protected compounds of Formula 1 were obtainedaccording to Scheme 5 as follows:

[0211] General Procedure

[0212] Several of the amino-acid compounds (HCl salt) of Formula 1 (madeas shown above in Example II) were respectively dissolved in a solutionof NaHCO₃ (10 mL/mmol) and a solution of BOC₂O in dioxan (10 mL/mmol)was added to each. Each mixture was stirred for 0.5 h and then dilutedwith H₂O and AcOEt (10 mL/mmol).

[0213] After extraction the aqueous layer for each was extracted withAcOEt (10 mL/mmol, twice). The combined organic layers were washed byH₂O (10 mL/mmol). The aqueous phase was acidified with a 2N HCl solutionto pH-2 to 4 and extracted with AcOEt (10 mL/mmol, twice). The combinedorganic layers were dried over Na₂SO₄ and concentrated to lead to thedesired products of N-protected Formula 1 as follows:

[0214] 54% yield

[0215] H1 NMR (CDCl3, 300 MHz, racemic): δ 7.33-7.14 (m, 5H), 5.40 (brs, 1H), 5.10 (br s, 1H), 4.20 (dd, 1H, 8.6-5.8 Hz), 3.66 (m, 1H), 3.10(dd, 1H, 13.2-5.8 Hz), 2.95 (dd, 1H, 13.2-8.6 Hz), 1.85-0.78 (m, 10H),1.41 (s, 9H).

[0216] 15% yield.

[0217] H1 NMR (CD₃OD, 300 MHz): δ 1.96 (m, 2H), 1.78 (m, 2H), 1.64-1.48(m, 4H), 1.43 (s, 9H). MS (ESP+) m/z 266.11 (M+Na).

[0218] 46% yield.

[0219] H1 NMR (CD₃OD, 300 MHz): δ 3.76 (dt, 2H, 11.9-4.0 Hz), 3.65 (td,2H, 11.9-4.0 Hz), 2.07 (m, 2H), 1.92 (m, 2H), 1.42 (s, 9H). MS (ESP+)m/z 268.07 (M+Na).

[0220] 95% yield.

[0221] H1 NMR (CD₃OD, 300 MHz): δ 3.89 (dd, 1H, 8.2-4.8 Hz), 1.81 (m,1H), 1.65 (m, 1H), 1.44 (s, 9H), 0.96 (t, 3H, 7.4 Hz). α_(D)=+13(c=0.15, ethanol). MS (ESP+) m/z 226.02 (M+Na).

[0222] 92% yield.

[0223] H1 NMR (CD₃OD, 300 MHz): δ 7.30-7.14 (m, 5H), 4.33 (dd, 1H,9.1-5.1 Hz), 3.14 (dd, 1H, 13.3-5.1 Hz), 2.89 (dd, 1H, 13.3-9.1 Hz),1.36 (s, 9H). α_(D)=−10 (c=0.2, Ethanol). MS (ESP+) m/z 288.11 (M+Na).

[0224] 32% yield.

[0225] H1 NMR (DMSO-d6, 300 MHz): δ 7.12-7.04 (m, 5H), 4.06 (m, 1H),2.99 (m, 1H), 2.79 (m, 1H). MS (ESP+) m/z 258.05 (M+Na).

[0226] MS (ESP) m/z 258.05 (M+Na).

[0227] It will be understood that various details of the invention maybe changed without departing from the scope of the invention.Furthermore, the above description is for the purpose of illustrationonly, and not for the purpose of limitation—the invention being definedby the claims.

What is claimed is:
 1. A compound comprising Formula 1

where R¹, R², and R³ are the same or different and are selected from:(f) H, with the proviso that at least one of R² and R³ is not H, (g)mono-, di-, and tri-substituted aryl, and (h) C₁-C₁₀ alkyl, C₁-C₁₀substituted alkyl, C₁-C₁₀ substituted alkyl-aryl, C₁-C₁₀ substitutedalkenyl, and C₁-C₁₀ substituted alkenyl aryl, where the substituents of(b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro,cyano, amino, C₁-C₁₀ alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl,C₁-C₁₀ alkylamino, C₁-C₁₀ aminoalkyl aryl, C₁-C₁₀ aminocarbonyl, C₁-C₁₀aminocarbonylalkyl-aryl, C₁-C₁₀ thioalkyl, C₁-C₁₀ thioalkyl-aryl, C₁-C₁₀alkylsulfoxide, C₁-C₁₀ alkylsulfone, C₁-C₁₀ alkylsulfonamide, C₁-C₁₀alkylsulfonamide aryl, C₁-C₁₀ alkylsulfoxide aryl, C₁-C₁₀ alkylsulfonearyl, C₁-C₁₀ alkyl, aminocarbonylamino C₁-C₁₀ alkyl, C₁-C₁₀ alkylaminocarbonylamino C₁-C₁₀ alkyl aryl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀alkyl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀ alkyl aryl, C₁-C₁₀ carboxyalkyl,C₁-C₁₀ carboxyalkyl aryl, C₁-C₁₀ carbonylalkyl, C₁-C₁₀ carbonylalkylaryl, C₁-C₁₀ alkyloxycarbonylamino alkyl, C₁-C₁₀ alkyloxycarbonylaminoalkyl aryl, guanidino, C₁-C₁₀ alkylCOOH, C₁-C₁₀ alkylCONH₂, C₁-C₁₀alkenylCOOH, C₁-C₁₀ alkenyl CONH₂, and where the aryl group of (b) and(c) is selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl,furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyt, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl; and whereR⁴ and R⁵ are the same or different and are selected from: (i) H, and(j) an amine protecting group.
 2. The compound of claim 1, where theamine protecting group is selected from phenyl, cyclohexenyl,cyclohexyl, t-butyl, 9-fluorenylmethylcarbonyl, tert-butyloxycarbonyl,allyloxycarbonyl, and benzyloxycarbonyl.
 3. The compound of claim 1,where the groups R² and R³ are joined together to form cyclic compoundswith a ring system as represented by Formula 1a

where the ring system has a ring size of 3 to 8 members.
 4. The compoundof claim 3, where the ring system is selected from: (a) mono-, di-,tri-, or tetra-substituted cyclopropenyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl as shown in compounds ofFormulae 1b and 1c

(b) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl as shown incompounds of Formula 1d

 (c) mono-, di-, tri- or tetra-substituted heterocyclic compounds ofFormulae 1e and 1f, where A is O, S, SO, SO₂ NH, SO₂NHR⁸, NCONHR⁸,NCOOR⁸, or NR⁸,

 and where R⁶, R⁷, R⁸, R⁹ and R¹⁰ of Formulae 1a-1f are the same ordifferent and are selected from: (d) H, (e) mono-, di-, andtri-substituted aryl, and (f) C₁-C₁₀ substituted alkyl,C₁-C₁₀-substituted alkyl-aryl C₁-C₁₀ substituted alkenyl, and C₁-C₁₀substituted alkenyl aryl, where the substituents of (e) and (f) areselected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino,C₁-C₁₀ alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl, C₁-C₁₀alkylamino, C₁-C₁₀ aminoalkyl aryl, C₁-C₁₀ aminocarbonyl, C₁-C₁₀aminocarbonylalkyl-aryl, C₁-C₁₀ thioalkyl, C₁-C₁₀ thioalkyl-aryl, C₁-C₁₀alkylsulfoxide, C₁-C₁₀ alkylsulfone, C₁-C₁₀ alkylsulfonamide, C₁-C₁₀alkylsulfonamide aryl, C₁-C₁₀ alkylsulfoxide aryl, C₁-C₁₀ alkylsulfonearyl, C₁-C₁₀ alkyl, aminocarbonylamino C₁-C₁₀ alkyl, C₁-C₁₀ alkylaminocarbonylamino C₁-C₁₀ alkyl aryl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀alkyl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀ alkyl aryl, C₁-C₁₀ carboxyalkyl,C₁-C₁₀ carboxyalkyl aryl, C₁-C₁₀ carbonylalkyl, C₁-C₁₀ carbonylalkylaryl, C₁-C₁₀ alkyloxycarbonylamino alkyl, C₁-C₁₀ alkyloxycarbonylaminoalkyl aryl, guanidino, C₁-C₁₀ alkylCOOH, C₁-C₁₀ alkylCONH₂, C₁-C₁₀alkenylCOOH, C₁-C₁₀ alkenyl CONH₂, and where the aryl groups of (e) and(f) are selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl,furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazoiyl, benthiazolyl, and benzoxazolyl.
 5. Amethod for making a compound of Formula 1

where R¹, R², and R³ are the same or different and are selected from:(a) H, with the proviso that at least one of R² and R³ is not H, (b)mono-, di-, and tri-substituted aryl, and (c) C₁-C₁₀ alkyl, C₁-C₁₀substituted alkyl, C₁-C₁₀ substituted alkyl-aryl, C₁-C₁₀ substitutedalkenyl, and C₁-C₁₀ substituted alkenyl aryl, where the substituents of(b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro,cyano, amino, C₁-C₁₀ alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl,C₁-C₁₀ alkylamino, C₁-C₁₀ aminoalkyl aryl, C₁-C₁₀ aminocarbonyl, C₁-C₁₀aminocarbonylalkyl-aryl, C₁-C₁₀ thioalkyl, C₁-C₁₀ thioalkyl-aryl, C₁-C₁₀alkylsulfoxide, C₁-C₁₀ alkylsulfone, C₁-C₁₀ alkylsulfonamide, C₁-C₁₀alkylsulfonamide aryl, C₁-C₁₀ alkylsulfoxide aryl, C₁-C₁₀ alkylsulfonearyl, C₁-C₁₀ alkyl, aminocarbonylamino C₁-C₁₀ alkyl, C₁-C₁₀ alkylaminocarbonylamino C₁-C₁₀ alkyl aryl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀alkyl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀ alkyl aryl, C₁-C₁₀ carboxyalkyl,C₁-C₁₀ carboxyalkyl aryl, C₁-C₁₀ carbonylalkyl, C₁-C₁₀ carbonylalkylaryl, C₁-C₁₀ alkyloxycarbonylamino alkyl, C₁-C₁₀ alkyloxycarbonylaminoalkyl aryl, guanidino, C₁-C₁₀ alkylCOOH, C₁-C₁₀ alkylCONH₂, C₁-C₁₀alkenylCOOH, C₁-C₁₀ alkenyl CONH₂, and where the aryl group of (b) and(c) is selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl,furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl; and whereR⁴ and R⁵ are the same or different and are selected from: (d) H, and(e) an amine protecting group; said method comprising: (i) reacting anamino acid/chiral auxiliary or a salt thereof, a convertible isocyanide,and at least one of an aldehyde and a ketone, in an alcohol or analcohol-containing solvent to obtain a compound of Formula 2

 and (ii) subjecting the compound of Formula 2 to aryl amine/hydrolysis,including catalytic hydrogenation, and to amide cleavage/hydrolysis, toobtain the compound of Formula
 1. 6. The method of claim 5, where theamine protecting group is selected from phenyl, cyclohexenyl,cyclohexyl, t-butyl, 9-fluorenylmethylcarbonyl, tert-butyloxycarbonyl,allyloxycarbonyl, and benzyloxycarbonyl.
 7. The method of claim 5, wherethe groups R² and R³ are joined together to form cyclic compound with aring system as represented by Formula 1a

where the ring system has a ring size of 3 to 8 members.
 8. The methodof claim 7, where the ring system is selected from: (a) mono-, di-,tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl as shown in compounds ofFormulae 1b and 1c

 (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl as shown incompounds of Formula 1d

 (c) mono-, di-, tri- or tetra-substituted heterocyclic compounds ofFormulae 1e and 1f, where A is O, S, SO, SO₂ NH, SO₂NHR⁸, NCONHR⁸,NCOOR⁸, or NR⁸,

 and where R⁶, R⁷, R⁸, R⁹ and R¹⁰ of Formulae 1a-1f are the same ordifferent and are selected from: (d) H, (e) mono-, di-, andtri-substituted aryl, and (f) C₁-C₁₀ substituted alkyl,C₁-C₁₀-substituted alkyl-aryl C₁-C₁₀ substituted alkenyl, and C₁-C₁₀substituted alkenyl aryl, where the substituents of (e) and (f) areselected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino,C₁-C₁₀ alkyloxy, C₁-C₁₀ alkyloxy aryl, C₁-C₁₀ aminoalkyl, C₁-C₁₀alkylamino, C₁-C₁₀ aminoalkyl aryl, C₁-C₁₀ aminocarbonyl, C₁-C₁₀aminocarbonylalkyl-aryl, C₁-C₁₀ thioalkyl, C₁-C₁₀ thioalkyl-aryl, C₁-C₁₀alkylsulfoxide, C₁-C₁₀ alkylsulfone, C₁-C₁₀ alkylsulfonamide, C₁-C₁₀alkylsulfonamide aryl, C₁-C₁₀ alkylsulfoxide aryl, C₁-C₁₀ alkylsulfonearyl, C₁-C₁₀ alkyl, aminocarbonylamino C₁-C₁₀ alkyl, C₁-C₁₀ alkylaminocarbonylamino C₁-C₁₀ alkyl aryl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀alkyl, C₁-C₁₀ alkyloxycarbonyl C₁-C₁₀ alkyl aryl, C₁-C₁₀ carboxyalkyl,C₁-C₁₀ carboxyalkyl aryl, C₁-C₁₀ carbonylalkyl, C₁-C₁₀ carbonylalkylaryl, C₁-C₁₀ alkyloxycarbonylamino alkyl, C₁-C₁₀ alkyloxycarbonylaminoalkyl aryl, guanidino, C₁-C₁₀ alkylCOOH, C₁-C₁₀ alkylCONH₂, C₁-C₁₀alkenylCOOH, C₁-C₁₀ alkenyl CONH₂, and where the aryl groups of (e) and(f) are selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl,furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl.
 9. Themethod of claim 5, where the amino acid/chiral auxiliary is phenylglycine, the convertible isocyanide is isocyanide, the alcohol ismethanol, and the catalytic hydrogenation employs Pd(OH)₂ for acatalyst.
 10. The method of claim 5, where step (ii) comprises that thearyl amine/hydrolysis and the amide cleavage/hydrolysis are followed byan amine protection reaction to place at least one amine protectinggroup on the N of Formula
 1. 11. The compound of claim 1, comprising acompound selected from the group consisting of:


12. The method of claim 5, where Formula 1 comprises a compound selectedfrom the group consisting of: